Targeted inhibition of Axl receptor tyrosine kinase ameliorates anti-GBM-induced lupus-like nephritis

Abstract

Glomerulonephritis (GN) is a typical lesion in autoantibody and immune complex disorders, including SLE. Because the Gas6/Axl pathway has been implicated in the pathogenesis of many types of GN, targeting this pathway might ameliorate GN. Consequently, we have studied the efficacy and mechanism of R428, a potent selective Axl inhibitor, in the prevention of experimental anti-GBM nephritis. Axl upregulation was investigated with Sp1/3 siRNA in the SV40-transformed mesangial cells. For Axl inhibition, a daily dose of R428 (125 mg/kg) or vehicle was administered orally. GN was induced with anti-GBM sera. Renal disease development was followed by serial blood urine nitrogen (BUN) determinations and by evaluation of kidney histology at the time of sacrifice. Axl-associated signaling proteins were analyzed by Western blotting and inflammatory cytokine secretion was analyzed by Proteome array. SiRNA data revealed the transcription factor Sp1 to be an important regulator of mesangial Axl expression. Anti-GBM serum induced severe nephritis with azotemia, protein casts and necrotic cell death. R428 treatment diminished renal Axl expression and improved kidney function, with significantly decreased BUN and glomerular proliferation. R428 treatment inhibited Axl and significantly decreased Akt phosphorylation and renal inflammatory cytokine and chemokine expression; similar effects were observed in anti-GBM antiserum-treated Axl-KO mice. These studies support a role for Axl inhibition in glomerulonephritis.

AXL targeting reduces fibrosis development in experimental unilateral ureteral obstruction

“…; Zhen et al. ). However, the effect of AXL RTK inhibition in kidney fibrosis remains to be a relatively understudied area (Batchu et al.…”

Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma

“…Increasing data have shown that kinase-dependent activation of tumorigenesis and therapeutic resistance is one of the major causes for GBM tumor recurrence, indicating that aberrant enhanced kinase activity could be a potential predictive biomarker for GBM. 4,[17][18][19] In this study, to further investigate prognostic biomarkers for glioma, kinome-wide screening was first performed with 3 GEO datasets (Mao et al, 20 2015, Tso et al, 21 2015, and Wang et al, 22 2017). TRIB2 and MAP3K1 were identified as genes that are correlated with the pathology and survival of glioma.…”

The AP-1 complex regulates AXL expression and determines sensitivity to PI3Kα inhibition in esophagus and head and neck squamous cell carcinoma

“…Three of the 41 TF were predicted to have binding sites on AXL promotor (QIAGEN-transcription factor analysis); AP-1, MYC, and MYC Associated Zinc Finger (Figure 2.B-C). SP1 transcription factor (previously reported to regulate AXL expression (20,25)) was upregulated in only in KYSE180 Res cells but not in CAL33 Res cells. Moreover, we observed an inverse correlation between AXL and microphthalmia-associated transcription factor (MITF) as previously reported for resistance to multiple targeted drugs in melanoma (23,26,27) (Figure 2 Table 1).…”

“…WB and qPCR analyses confirmed the upregulation of c-JUN in BYL719-resistant vs. sensitive cells, with c-JUN upregulation being associated with AXL overexpression ( Figure 2B and C). The SP1 TF [previously reported to regulate AXL expression (20,25)] was upregulated in KYSE180 Res cells but not in CAL33 Res cells. In addition, we found an inverse correlation between AXL and the microphthalmia-associated transcription factor (MITF) ( Figure 2B), in agreement with previous reports (23,26,27).…”